Details
Stereochemistry | ACHIRAL |
Molecular Formula | C32H29N5O2 |
Molecular Weight | 515.605 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1C=C(C2=C1C=CC=C2)C3=C(C(=O)NC3=O)C4=CN(C5CCN(CC6=CC=CC=N6)CC5)C7=C4C=CC=C7
InChI
InChIKey=AXRCEOKUDYDWLF-UHFFFAOYSA-N
InChI=1S/C32H29N5O2/c1-35-19-25(23-9-2-4-11-27(23)35)29-30(32(39)34-31(29)38)26-20-37(28-12-5-3-10-24(26)28)22-13-16-36(17-14-22)18-21-8-6-7-15-33-21/h2-12,15,19-20,22H,13-14,16-18H2,1H3,(H,34,38,39)
Molecular Formula | C32H29N5O2 |
Molecular Weight | 515.605 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.
Originator
Sources: http://adisinsight.springer.com/drugs/800015989
Curator's Comment: # Eli Lilly
Approval Year
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1310 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16943527 |
700 mg 1 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ENZASTAURIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
17400 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16943527 |
700 mg 1 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ENZASTAURIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
14.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16943527 |
700 mg 1 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ENZASTAURIN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/17671157 |
ENZASTAURIN plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes | ||||
yes | ||||
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Hypoxia, tumor endothelium, and targets for therapy. | 2005 |
|
The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. | 2005 Aug 15 |
|
Perspectives in central nervous system malignancies. | 2006 Jun |
|
Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. | 2006 Sep 1 |
|
Inorganic pyrophosphate generation by transforming growth factor-beta-1 is mainly dependent on ANK induction by Ras/Raf-1/extracellular signal-regulated kinase pathways in chondrocytes. | 2007 |
|
Survival improvement in thoracic cancer: progress from the last decade and beyond. | 2007 Aug |
|
Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer. | 2007 Aug 1 |
|
Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. | 2007 Feb |
|
Safety, tolerability, QTc evaluation, and pharmacokinetics of single and multiple doses of enzastaurin HCl (LY317615), a protein kinase C-beta inhibitor, in healthy subjects. | 2007 Sep |
|
Chemoradiotherapy in malignant glioma: standard of care and future directions. | 2007 Sep 10 |
|
Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Conclusion. | 2008 |
|
Protein kinase C isozymes as therapeutic targets for treatment of human cancers. | 2008 |
|
Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs. | 2008 Aug 5 |
|
A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors. | 2008 Jan |
|
Targeted treatment and new agents in diffuse large B-cell lymphoma. | 2008 Jul |
|
The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines. | 2008 Jul |
|
[Protein kinases C: a new cytoplasmic target]. | 2008 Jul-Aug |
|
Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C. | 2008 Jun |
|
Involvement of protein kinase C beta-extracellular signal-regulating kinase 1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion. | 2008 Mar |
|
[Recent therapeutic progress in non-Hodgkin lymphoma: focusing on diffuse large B-cell lymphoma and follicular lymphoma]. | 2008 Oct |
|
Novel therapies in breast cancer: what is new from ASCO 2008. | 2008 Oct 1 |
|
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells. | 2008 Sep 2 |
|
The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells. | 2008 Sep 8 |
|
Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents. | 2009 |
|
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling. | 2009 Feb 12 |
|
Antiangiogenic drugs in ovarian cancer. | 2009 Jan 13 |
|
[Role of PKCbeta in the malignant tumors and enzastaurin, a PKCbeta inhibitor]. | 2009 May |
|
A phase I trial of enzastaurin in patients with recurrent gliomas. | 2009 May 15 |
|
Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths. | 2009 May 28 |
|
Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70. | 2010 Jan |
|
Protein kinase Cbeta modulates ligand-induced cell surface death receptor accumulation: a mechanistic basis for enzastaurin-death ligand synergy. | 2010 Jan 8 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT00332202
1125 mg loading dose then 500 mg, oral, daily, until disease progression or maximum of 3 years
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21606156
In the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 uM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin.
Substance Class |
Chemical
Created
by
admin
on
Edited
Mon Mar 31 18:26:16 GMT 2025
by
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on
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Record UNII |
UC96G28EQF
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Record Status |
Validated (UNII)
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Record Version |
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FDA ORPHAN DRUG |
849821
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FDA ORPHAN DRUG |
277209
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NCI_THESAURUS |
C2089
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FDA ORPHAN DRUG |
208505
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DTXSID5044029
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CHEMBL300138
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HI-222
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170364-57-5
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ENZASTAURIN
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SUB33466
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UC96G28EQF
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C504878
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DB06486
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C77392
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m4926
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PRIMARY | Merck Index |
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ACTIVE MOIETY |